Understanding the regulatory circuits that govern cellular energy and glucose metabolism has been a focus of research interest in the past decade. Recent studies have implicated transcription coactivators of the PGC-1 family, in particular PGC-1α and PGC-1β, as important regulators of mitochondrial biogenesis and cellular respiration in several cell types (Kelly, D. P., and Scarpulla, R. C. (2004) Genes Dev 18, 357-368; Puigserver, P., and Spiegelman, B. M. (2003) Endocr Rev 24, 78-90.). Notably, the expression of PGC-1α has been found to be dysregulated in diabetic liver and skeletal muscle, tissues critical for maintaining normal blood glucose levels, while PGC-1β mRNA levels are also lowered in diabetic muscle (Mootha et al. (2003) Nat Genet 34, 267-273; Patti, M. et al. (2003) Proc Natl Acad Sci USA 100, 8466-8471; Yoon J. C., et al. (2001) Nature 413, 131-138). PGC-1α was initially identified as a cold-inducible coactivator for PPARγ in brown fat (Puigserver et al. (1998) Cell 92, 829-839). Subsequent studies revealed that PGC-1α is able to bind to and augment transcriptional activities of many nuclear receptors and several other transcription factors outside the nuclear receptor superfamily. Adenoviral-mediated or transgenic expression of PGC-1α in cultured cells and in vivo leads to activation of mitochondrial biogenesis and increases in cellular respiration (Lehman et al., (2000) J Clin Invest 106, 847-856; Lin et al. (2002b) Nature 418, 797-801; St-Pierre et al. (2003) J Biol Chem 278, 26597-26603; Wu et al. (1999) Cell 98, 115-124). Consistent with a regulatory role in the cellular adaptations to increased energy requirements, the expression of PGC-1α itself is highly regulated in response to nutritional and environmental stimuli. For example, PGC-1α mRNA is strongly induced in brown fat by cold exposure and in skeletal muscle following physical activity (Baar et al. (2002) Faseb J 16, 1879-1886; Goto et al. (2000) Biochem Biophys Res Commun 274, 350-354; Puigserver et al. (1998) Cell 92, 829-839). Increased PGC-1α levels in these tissues lead to enhanced mitochondrial electron transport activities that enable cells to meet rising energy demands, such as during adaptive thermogenesis in brown fat and contraction in muscle.
In addition to its role in mitochondrial biology, PGC-1α also regulates several key metabolic programs that go beyond simple mitochondrial biogenesis and oxidative phosphorylation. For example, PGC-1α drives expression of myofibrillar proteins characteristic of slow-twitch muscle fibers when expressed in fast-twitch muscle beds of transgenic mice (Lin et al. (2002b) Nature 418, 797-801). In the liver, PGC-1α mRNA level is rapidly induced following short-term fasting (Yoon et al. (2001) Nature 413, 131-138). Adenoviral-mediated expression of PGC-1α in cultured primary hepatocytes and in live rats leads to activation of the entire program of gluconeogenesis and increased glucose production (Yoon et al. (2001) Nature 413, 131-138). In all of these cases, PGC-1α interacts with cell-selective transcription factors to execute these tissue-specific functions, such as MEF2c in skeletal muscle and HNF4α and FOXO1 in the liver.